Oncotarget

Research Papers:

Type II RAF inhibitor causes superior ERK pathway suppression compared to type I RAF inhibitor in cells expressing different BRAF mutant types recurrently found in lung cancer

Amir Noeparast, Philippe Giron, Sylvia De Brakeleer, Carolien Eggermont, Ulrike De Ridder, Erik Teugels and Jacques De Grève _

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Oncotarget. 2018; 9:16110-16123. https://doi.org/10.18632/oncotarget.24576

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Abstract

Amir Noeparast1,*, Philippe Giron1,*, Sylvia De Brakeleer1, Carolien Eggermont1, Ulrike De Ridder1, Erik Teugels1 and Jacques De Grève2

1Laboratory of Molecular Oncology, Vrije Universiteit, Brussels, Belgium

2Department of Medical Oncology, Oncologisch Centrum, Universitair Ziekenhuis Brussel, Brussels, Belgium

*These authors contributed equally to this work

Correspondence to:

Jacques De Grève, email: jacques.degreve@uzbrussel.be

Erik Teugels, email: erik.teugels@uzbrussel.be

Keywords: non-small cell lung cancer; Dabrafenib; Trametinib; AZ628; BRAF

Received: April 19, 2017     Accepted: February 20, 2018     Epub: February 27, 2018     Published: March 23, 2018

ABSTRACT

A large fraction of somatic driver BRAF mutations in lung cancer are non-V600 and impaired-kinase. Non-V600 BRAF mutations predict sensitivity to combination of a type I RAF inhibitor, Dabrafenib, and a MEK inhibitor, Trametinib. Singly, Dabrafenib only weakly suppresses mutant BRAF-induced ERK signaling and can induce ERK paradoxical activation in CRAF-overexpressing cells. The present study compared the effects of Dabrafenib and a type II RAF inhibitor, AZ628, on ERK activity in HEK293T cells expressing several tumor-derived BRAF mutants, and in a non-V600 and impaired-kinase BRAF-mutant lung cancer cell line (H1666). Unlike Dabrafenib, AZ628 did not induce paradoxical ERK activation in CRAF-overexpressing cells and BRAF-mutant cells overexpressing CRAF were more responsive to AZ628 compared to Dabrafenib in terms of ERK inhibition. AZ628 inhibited ERK more effectively than Dabrafenib in both H1666 cells and HEK293T cells co-expressing several different BRAF-mutants with CRAF. Similarly, AZ628 plus Trametinib had better MEK-inhibitory and pro-apoptotic effects in H1666 cells than Dabrafenib plus Trametinib. Moreover, prolonged treatment of H1666 cells with AZ628 plus Trametinib produced greater inhibition of cell growth than Dabrafenib plus Trametinib. These results indicate that AZ628 has greater potential than Dabrafenib, both as a single agent and combined with Trametinib, for the treatment of non-V600 BRAF mutant lung cancer.


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